Depression and anxiety disorders are extremely common, with a lifetime prevalence of approximately 17%. These disorders are often chronic and are associated with long duration of episodes and frequent relapses. Indeed, the likelihood of recurrence is greater than 50% (Angst et al., J. Clin. Psychiatry 1999, 6, 5). Examples of depression disorders include major depressive disorder, dysthymia, bipolar disorder, seasonal affective disorder, cyclothymia, and postnatal depression. Examples of anxiety disorders include panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, specific phobias, and generalized anxiety disorder. These disorders are often characterized by both psychosocial and physical impairment, with a high suicide rate among those affected. Because most antidepressants with clinical efficacy act upon monoamines (primarily norepinephrine and serotonin), much research on depression and anxiety has focused upon interactions between these neurotransmitters and their reuptake transporters and receptor proteins.
While the pharmacological action of antidepressants occurs within minutes to hours after administration, the clinical effect and alleviation of symptoms can take up to two weeks following chronic administration. This discrepancy suggests that focusing on monoamine depletion as the underlying pathogenesis of depression may be oversimplified. Several neurotransmitters and neuropeptides are involved in the complex neuroanatomical pathways in anxiety. Intracellular signaling pathways involved in stress-related disorders appear to be intimately associated with the metabolic integrity and capacity of mitochondria to maintain energetic parameters and ultimately cellular stability. Future therapeutic intervention may lie in better understanding this relationship. Treating mitochondrial function may therefore offer a novel avenue for the development of therapies for the treatment of depression- and anxiety-related disorders.
Creatine, omega-3 fatty acids, and citicoline all serve to augment brain mitochondrial function by different mechanisms of action. Creatine plays an essential role in energy metabolism by interconversion of its high-energy phosphorylated analog phosphocreatine, which serves as a short-term buffer to regenerate adenosine triphosphate (Beard et al., J. Neurochem. 2010, 115, 297). The omega-3 fatty acids exist at high levels in mitochondrial phospholipids, suggesting that they are essential for the mitochondrial oxidative phosphorylation system to work efficiently (Eckert et al., Prostaglandins, Leukotrienes, and Essential Fatty Acids 2013, 88, 105). Citicoline has been shown to directly increase frontal lobe levels of both phosphocreatine and adenosine triphosphate following chronic oral administration (Silveri et al., NMR in Biomed. 2008, 21, 1066).
Despite these beneficial effects, the combinatorial effect of all three substances in unison has not been studied previously. Thus, there remains a need for methods and compositions that overcome these deficiencies and that effectively treat depression in humans. These needs and other needs are satisfied by the present invention.